Pulmonary delivery of peptide and protein biotherapeutics (and also non-peptide drugs) is a rapidly growing area in drug delivery. To this end, aerosol preparations of such medicaments have been developed as a means of conveyance to the respiratory system. In order for aerosols to be effective, several factors must be considered in their formulation. One factor to consider is the intended application of the aerosol drug, i.e. whether the drug is intended for systemic or topical application and/or for sustained or immediate release. For example, effective systemic administration via the pulmonary route requires delivery of the drug to the deep lung (ie. alveoli) where diffusion and phagocytosis have been proposed as primary mechanisms for drug absorption. In this situation, it is preferrable that the aerosol be formulated to release particles between 1-5 .mu.m in size in order to overcome the lung's formidable barriers to particle deposition. In contrast, larger sized particles may be suitable for topical application of a drug where deposition of a drug in the central airways may be warranted. Other factors such as particle aggregation and drug stability must also be considered in the formulation development.
Aerosols are generally described as dispersions of medicament in a continuous phase. Preparations currently in use include both suspension and solution aerosol formulations. Suspension aerosols contain solid particles of a medicament of interest. The particles of the suspension must be pre-milled to a particular size during formulation and these particles are released upon use. In contrast, solution aerosols contain dissolved medicaments which are released from the dispenser in the form of a mist. Due to the large surface area of mist, the propellant or continuous phase (i.e. the formulation component in which the drug is either dispersed or solubilized) evaporates almost instantly leaving the residual medicament in the form of solid particles. Both suspension and solution aerosols have been used effectively to deliver certain medicaments systemically, examples being ergotamine tartrate, deoxyribonuclease and leuprolide acetate. Solution aerosols, however, have certain advantages over suspension aerosols in that they form finer particles (that can more readily reach the alveoli), they avoid the need for complex milling steps and they are cheaper to manufacture. In other cases, suspension aerosols may be more advantageous, by offering better chemical stability than their equivalent solution aerosols (possibly due to reduced oxidative or hydrolytic reactions in the formulation). Thus, there is a need for both solution and suspension aerosols depending on the intended use of the medicament contained therein as well as its chemical and physical properties.
In pressurized aerosols, also referred to as metered dose inhalers (MDIs), a physiologically inert propellant of high vapor pressure, generally a halogenated alkane, is used to discharge a medication. Use of an appropriate formulation-compatible metering valve allows delivery of precise amount of medication with each actuation. The propellants of choice for MDI devices have historically been chlorofluoro-carbons, such as Propellant 11 (trichlorofluoromethane), Propellant 12 (dichlorodifluoromethane) and Propellant 114 (dichlorotetrafluoroethane). In recent years however, there have been growing concerns that chlorofluorocarbon ("CFC") propellants have detrimental environmental effects, and in particular that they interfere with the protective upper-atmosphere ozone layer. Under an international accord (the Montreal Protocol), the use of CFC propellants phased out will be prohibited by the start of the year 1996, and possibly sooner. Alternative propellant vehicles are being developed which exhibit little or no ozone depletion potential (ODP). Such alternative propellants (referred to herein as "non-chlorofluorocarbons" ("non-CFC) or "non-chlorinated propellants) include two hydrofluorocarbons--HFC-134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane). These propellants have negligible ODP and are currently undergoing safety and environmental testing.
Unfortunately, many surfactants which are traditionally used in MDI formulations with known CFC propellants have been found to be immiscible, and therefore incompatible, with these new, non-CFC propellants. Such surfactants are generally necessary to prevent aggregation (in the form of "caking" or crystallization, for example) of the medicinally active compound in the reservoir of the inhaler, to facilitate uniform dosing upon aerosol administration, and to provide an aerosol spray discharge having a favorable respirable fraction (that is, a particle size distribution such that a large portion of the discharge reaches the alveoli where systemic absorption takes place, and thus produces high lung deposition efficiencies). To overcome this incompatibility, it has previously been taught by Purewal et al. (EP-A-372777) to include cosolvents such as ethanol with the non-CFC propellants so as to blend the surfactants into the formulation. Another suggested approach has been to emulsify the MDI medicament in the presence of a surfactant with low-vapor pressure additives, such as polyhydroxy alcohols (for example propylene glycol).
Such cosolvents or additives may of course be physiologically active, and in some instances may not be tolerated by the user of an MDI medication. In addition, they may lead to increased instability of drug. There is therefore a need for MDI formulations compatible with non-CFC propellants which prevent aggregation of drug particles without the use of cosolvents or similar carrier additives, and which provide uniformity of dosing and a favorable respirable fraction.
Surprisingly, it has now been found that certain naturally occurring vegetable oils such as olive oil, safflower oil, soybean oil and the like are capable of stabilizing MDI formulations, especially those utilizing non-ozone-depleting propellants such as HFC-134a and HFC-227ea so as to (i) prevent aggregation of medicament, (ii) provide dosing uniformity, and (iii) afford improved lung deposition efficiency, preferably without the need for either surfactants or cosolvents. Additionally, these oils have the unexpected benefit of providing adequate lubrication for the valve used in an MDI product without the need for additional lubricants, thus aiding reliable functioning of the aerosol device throughout the life of the product. It has also been found that oils can be formulated to produce a clear solution product in the alternate non-CFC propellant either with or without additional surfactants.
Significant characteristics of vegetable oils are that: (i) they offer enhanced physical drug stability, (ii) they are non-ionic agents which do not chemically interact with drug; (iii) they have been used previously in oral and injectable liquid dosage forms, thereby establishing their physiological acceptability; (iv) they are highly soluble in HFC 134a; and (v) they may be formulated to produce either a stable suspension or a clear solution in the alternate propellant. Furthermore, solution formulations avoid the need for complex milling steps which increase the manufacturing cost of the product. Non-CFC formulations which include oils do not require the addition of (i) cosolvents like ethanol to blend the surfactant into the formulation, (ii) conventional surfactants such as sorbitan trioleate (SPAN 85.TM.), sorbitan monooleate and oleic acid, or (iii) protective colloids like sodium lauryl sulfate and cholesterol, yet provide good lung deposition efficiencies and respirable fractions comparable to those obtained with known CFC-propellant formulations. It is thus expected that aerosol formulations comprising such oils will be useful for the delivery of both peptide and non-peptide pharmaceutical medicaments for which MDI delivery is deemed preferable.